Proteins and peptides are becoming an important class of therapeutic agents. Despite their high biological activity and specificity, their therapeutic efficacy when delivered in native form is largely hindered by numerous limitations, including short circulation half-life, poor stability, low solubility and immunogenicity. Frequent administration of the agent may be required, which may increase cost, inconvenience and the risk of adverse reactions.
Conjugating biomolecules with stealth polymers has become a commonly used method to address these limitations. Polypeptide-polymer conjugates are conventionally synthesized using the “grafting to” method, in which the polymer is first pre-synthesized, and then conjugated to the polypeptide post-polymerizationally. Such an approach typically results in poor yield due to steric hindrance between the biomolecule and polymer and difficulty in product purification as a result of similar sizes and surface properties of the reactants and products. Additionally, conjugation is often done in a non-specific manner, by exploiting promiscuously distributed reactive side chains or residues that are only partially solvent accessible. As a result, large degree of heterogeneity is often found in the product, significantly compromising bioactivity.